Prediabetic and diabetic in vivo modification of circulating low-density lipoprotein attenuates its stimulatory effect on adrenal aldosterone and cortisol secretion

Abstract

Modification of low-density lipoprotein (LDL) and abnormal aldosterone and cortisol metabolism have been implicated in the pathogenesis of type 2 diabetes (DM2) and diabetic vascular disease. Since LDL serves as a major cholesterol source for adrenal steroidogenesis, we investigated whether LDL modification in prediabetic and diabetic subjects influences adrenocortical aldosterone and cortisol release. LDL was isolated from 30 subjects with normal glucose tolerance (NGT-LDL), 30 subjects with impaired glucose tolerance (IGT-LDL), and 26 patients with DM2 (DM2-LDL). Oxidation and glycoxidation characteristics of LDL apolipoprotein B100 of each individual was assessed by gas chromatography-mass spectrometry analysis. Human adrenocortical cells (NCI-H295R) were incubated for 24 h with 100 mg/ml LDL and after removal of supernatants stimulated for a further 24 h with angiotensin II (AngII). In supernatants, aldosterone and cortisol secretion was measured. IGT-LDL and DM2-LDL were substantially more modified than NGT-LDL. Each of the five measured oxidation/glycoxidation markers was significantly positively associated with glycemic control, measured as HbA 1c . LDL from all subjects stimulated both the basal and AngII-induced aldosterone and cortisol release from adrenocortical cells. However, hormone secretion was significantly inversely related to the degree of LDL oxidation/glycoxidation. We conclude that LDL modifications in IGT and DM2 subjects may have significant clinical benefits by counteracting prediabetic and diabetic overactivity of the renin-angiotensinaldosterone system and enhanced cortisol generation.

Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells

“…In fact, the MultiEthnic Study of Atherosclerosis demonstrated an association between high oxLDL and the severity of coronary calcification [47]. Furthermore, enhanced circulating levels of oxLDL have been found in patients with impaired glucose tolerance [17] and type 2 diabetes [18]. In our study, VSMCs isolated from diabetic rats tended to become easily calcified.…”

“…In vascular cells, increased oxidative stress reduces the availability of nitric oxide, potentiates redox-sensitive signal transduction, and is able to convert LDL into oxidised (ox)LDL, the latter representing a pivotal established risk factor for cardiovascular disease. Interestingly, enhanced circulating levels of oxLDL have been found in patients with impaired glucose tolerance [17] and type 2 diabetes [18]. Furthermore, oxidative stress and oxidised lipids may promote osteogenic differentiation under appropriate conditions [19][20][21][22].…”

Top-Down Lipidomics Reveals Ether Lipid Deficiency in Blood Plasma of Hypertensive Patients

“…Elevations in inflammatory lipids such as LPC and long-chain fatty acids will induce endothelial dysfunction and eventually lead to hypertension [34]. Alterations in insulin secretion and other hormones such as aldosterone and catecholamines induced by these lipid changes will likewise affect blood pressure regulation [35]–[37].…”

Effect of Spironolactone on Cardiovascular Complications Associated with Type-2 Diabetes in Rats

“…Thus, several mechanisms can be attributed for control in hyperglycemia by spironolactone and advanced studies are required to fi nd out specifi c mechanism. Impaired glucose tolerance and type 2 diabetes subjects are reported to exhibit enhanced circulating levels of oxidized LDL [ 27 ] . LDL modifi cation and overactivity of the RAAS has been related to the pathogenesis of type 2 diabetes [ 28 ] and its adverse cardiovascular consequences [ 27 ] .…”

“…Impaired glucose tolerance and type 2 diabetes subjects are reported to exhibit enhanced circulating levels of oxidized LDL [ 27 ] . LDL modifi cation and overactivity of the RAAS has been related to the pathogenesis of type 2 diabetes [ 28 ] and its adverse cardiovascular consequences [ 27 ] . In the current investigation, diabetic rats exhibited dyslipidemia which was signifi cantly controlled by the spironolactone treatment.…”